Hydrophobic-hydrophilic Alternation: An effective Pattern to de novo Designed Antimicrobial Peptides

Abstract

The antimicrobial peptide (AMP) is a class of molecules that are active against a variety of microorganisms, from bacterial and cancer cells to fungi. Most AMPs are natural products, as part of an organism's own defense system against harmful microbes. However, the growing prevalence of drug resistance has forced researchers to design more promising engineered antimicrobial agents. Inspired by the amphiphilic detergents, the hydrophobic-hydrophilic alternation pattern was considered to be a simple but effective way to de novo design AMPs. In this model, hydrophobic amino acids (leucine, isoleucine et al.) and hydrophilic amino acids (arginine, lysine et al.) were arranged in an alternating way in the peptide sequence. The majority of this type of peptides have a clear hydrophilic-hydrophobic interface, which allows the molecules to have good solubility in both water and organic solvents. When they come into contact with hydrophobic membranes, many peptides undergo a conformational transformation, facilitating themself to insert into the cellular envelope. Moreover, positive-charged peptide amphiphiles tended to have an affinity with negatively-charged membrane interfaces and further led to envelope damage and cell death. Herein, several typical design patterns have been reviewed. Though varying in amino acid sequence, they all basically follow the rule of alternating arrangement of hydrophilic and hydrophobic residues. Based on that, researchers synthesized some lead compounds with favorable antimicrobial activities and preliminarily investigated their possible mode of action. Besides membrane disruption, these AMPs are proven to kill microbes in multiple mechanisms. These results deepened our understanding of AMPs’ design and provided a theoretical basis for constructing peptide candidates with better biocompatibility and therapeutic potential

Fusion Expression of Peptides with AflR Binuclear Zinc Finger Motif and Their Enhanced Inhibition of Aspergillus flavus: A Study of Engineered Antimicrobial Peptides

“…flavus, as evidenced by reduced MIC values (Table ). This structural transformation is pivotal and aligns with the well-established theoretical models of AMP actions on cellular membranes . The engineered AMP CecXJ-37N exhibits an 11-fold increase in the α-helix ratio compared to the nonamidated isomer in a comparable environment at the prokaryotic membrane, showing a smaller MIC .…”

“…This structural transformation is pivotal and aligns with the well-established theoretical models of AMP actions on cellular membranes. 29 The engineered AMP CecXJ-37N exhibits an 11-fold increase in the α-helix ratio compared to the nonamidated isomer in a comparable environment at the prokaryotic membrane, showing a smaller MIC. 30 The stepwise arrangement, orientation, and permeabilization mechanisms of AMPs, predominantly based on the activity of α-helical AMPs, have been conceptualized in five models.…”

Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy

“…Although the exact process is not yet fully defined, studies performed on model membranes (e.g., liposomes) have shown that the positive charge is responsible for the initial interaction with the negatively charged membrane of microorganisms, whereas the hydrophobic portion is responsible for their insertion into the lipid bilayer [ 20 ]. Consequently, achieving the right balance between the hydrophilic and hydrophobic domains is key in determining the specificity of action of AMPs [ 21 ]. The positioning on the surface of the membrane and/or the incorporation into the membrane causes the disruption of membrane integrity with pore formation or membrane permeabilization followed by osmotic shock and loss of homeostasis [ 22 ].…”

Design Methods for Antimicrobial Peptides with Improved Performance

“…Furthermore, the amphipathic nature of many AMPs, characterized by spatially segregated hydrophobic and hydrophilic faces within their molecular structure ( Huan et al, 2020 ), is crucial for their antimicrobial activity. This amphipathicity enables insertions into microbial membranes while retaining solubility in aqueous environments ( Cheng & Zeng, 2022 ). Another key property of AMPs is their concise sequence length, typically ranging from 10 to 50 amino acid residues.…”

“…For example, the incorporation of non-natural amino acids, cyclization, and alternative delivery strategies (i.e., nanoparticle formulation) can enhance the stability of AMPs. The cationic charge of peptides can also be enhanced by incorporating positively charged amino acids, such as Lys and Arg, to increase the affinity of AMPs to the altered negative microbial surface charges ( Cheng & Zeng, 2022 ). Combination therapy with two or more AMPs or with an AMP and an antibiotic can increase the killing efficacy and reduce the likelihood of resistance development ( Sheard et al, 2019 ).…”